1, 2-disubstituted-4, 5-dihydroimidazoles



UNITED STATES PATENT OFFICE 1,2-DISUBSTITUTED-4,5:DIHYDBO- DVHDAZOLES Lucas 1?. Kyrides, Webster Groves, and Ferdinand B. Zienty, St. Louis, Mo., assignors to Monsanto Chemical Company, St. Louis, Mo., a corporation of Delaware No Drawing. Application August 13, 1943,

Serial No. 498,584

6 Claims. (01. 2260-30913) The present invention relates to the production of new therapeutic agents and insecticides'toxicants which are substituted imidazoline compounds, and comprises the'method of producing these compounds as well as the new products themselves.

According to the present invention, generally stated, new products which are of outstanding value in the treatment of various diseases are made by preparing substituted dihydroimidazoles of the type represented by the formula:

in which R represents an acyclic hydrocarbon radical having from 1 to carbon atoms in. its structure and R1 represents an acyclic hydrocarbon radical having from 10 to 16 carbon atoms in its structure. represented by B may be a straight chain alkyl radical such as the methyl, ethyl, propyl, butyl and amyl radicals, ora branched chain alkyl radical such as the isopropyl, tertiary butyl and isoamyl radicals. Likewise It may be an alkenyl radical having from 1 to 5 carbon atoms in its straight or branched chain structure, for example, the propenyl, butenyl and 'isobutenyl radicals. The acyclic hydrocarbon radical represented by R1 may be composed of a 'st'lfa'ightchain alkyl radical such as the decyl, undecyl, dodecyl, r

tridecyl, tetradecyl, pentadecyl and hexadecyl radicala or a straight chain alkenyl radical, such as the decenyl, undecenyl, dodecenyl, tridecenyl,

tetradecenyl, pentadecenyl and hexadecenyl radr icals in which one or more double bonds maybe located in various positions in the chain. The water-soluble salts of these compounds may be prepared and are also valuable therapeutic agents and insecticide toxicants. For example, the'hydrochlori'des, hydrobroinides and acetates and other salts may be employed.

The new products and their water-soluble salts may be administered orally or parenterally and have been found to be unusually effective in the treatment of various diseases. The organic and inorganic acid salts may beprepared by dis,- solving the products in an aqueous solution containing the stoichiometrical equivalent of a suitable acid, such as hydrochloric, hydrobromic, acetic acids, and the like, and the solution may be employed for parenteral administration. Also, the acid salts may be prepared during the synthesis of the imidazoline derivative or immedi- The acyclic hydrocarbon radial ately thereafter and beforethe productis isolated from the reaction mixture.

The products of the present invention haye also been found to possess utility as insecticides and toxicants for insecticide compositions,; such, as sprays and powders in which the compounds are blended with suitable wetting agents, fillers, solvents, adhesives, coating agents, repellents, and other ingredients employed in compoun r g insecticides.

The products of the present, invention may. be prepared by reacting ethylene diamine with a molecular equivalent or less of an acylating agent comprising an aliphatic monocarboxylicacid having as its alkyl residue one of the radicals def scribed hereinbefore in the definition of R1 with respect to the formula. The acid thus employed willbe cOmIQQsed of a straight 'chainallsyl residue of the properchain length together 'withabarboxylic acid group, thecarbon atom of which is not included in the contemplation'of the chain length hereinbefore described. ,In the place of the acid, the alkyl ester, such as the butyl ester, or desirably the methyl or ethyl ester, may' be employed, or the acyl halide such as the' acyl chloride, or the acid anhydri'dej""The resulting mono-acyl'aminoi derivative is then'condensed with the aid of 'a suitable mild dehydrating agent, such as powdered'calcium oxideto form the 2-nalkyl-4,5-dihydroimidazole. The derivative thus prepared is then reacted with an alkylating agent having as its alkyl or alkenyl residue one of.the residues described hereinbefore in the definition of R withrespect to the formula. The alkylating agent may be a mineral acid salt such as an alkyl sulfate or alkenyl sulfate. Also,"the alkylati'ng acid may be an alkyl halide or an alkenyl halide.

The product thus prepared is a substituted imidazoline' which corresponds to theformula herein-,

ethylene diamine was refluxed at 112 C; for

3 12 hours. The reaction mixture was transferred to a still and the alcohol and excess ethylene diamine were removed by distillation. The yield of crude N-dodecanoyl ethylene diamine was 172 grams. V

A mixture of 162 grams of crude N-dodecanoyl ethylene diamine and 187 grams of powdered calcium oxide was heated with stirring at 225 C. for 36 hours. The reaction mixture was cooled and extracted 3 times with about 350 cc. of alcohol at room temperature. The alcohol wasremoved by distillation and the product was distilled by reduced pressure. The boiling point of the product was 180-189 C./10 mm. The m. p. of the product was 81-83 C. The yield of produce was 98.5

grams.

The product was identified as 2-undecyl-4,5-dihydroimidazole. To 56.5 grams of 2-undecyl-4,5- dihydroimidazole was added 31.7 grams of dimethyl sulfate over a period of 32 minutes. The temperature of the reaction mixture was maintained at about 85 C. To the reaction mixture was added approximately 150 cc. of water and the mixture was stirred until the solid material had dissolved. A solution of 20 grams of 50% sodium hydroxideand approximately 150 cc. of butyl alcohol was added to the mixture with agitation. The mixture was then filtered, and the butyl alcohol layer of the filtrate was distilled to remove butyl alcohol and water. The residue was then distilled at reduced pressure to recover the product. The B. P. of the product was 167-1'l2/6 mm. The yield of product was 38% and the assay was 96.2%. The product was identified as 1-methyl-2-n-undecy1-4,5-dihydroimidazole. V

.. EXAMPLE II To 84.9 grams of 2-n-undecy1-4,5-dihydroimidazole heated to 140-150, was added dropwise 21.7 grams of n-amyl chloride. The temperature of the'reaction mixture was held at 147-154 C. for a total of 16 hours. The reaction mixture was then cooled to 60 C. A solution of 17.1 grams of 50% sodium hydroxide in approximately 150 cc. of water and approximately 150 cc. of butyl alcohol was added to the reaction mixture slowly with agitation. The mixture w as then agitated for 1 hour at room temperature and thereafter distilled to remove butyl alcohol and water. The residue was then distilled at reduced pressure to recover the product. The B. P. of the product Was"145-180 C./5 mm. The yield of product .was' 70.3% and the assay was substantially 100%. The product was identified as 2-n-amyl-2-n-undecyl-dihydroimidazole.

Y 7 v EXAMPLE III 1-methyl-2-n-decyl-4,5-dihydroimidazole orig-Neon,

E: C- CH:.(CHz)a.CHa

A mixture of 160.5 grams of the ethyl ester of n-undecanoic acid and 135 grams oi anhydrous ethylene diamine was reacted according to the method of Example I. The resulting N-undecanoyl ethylene diamine was condensed with anhydrous calcium oxide according to the method of Example I. The resulting 2-n-decyl-4, 5-dihy- I droimidazole was then reacted with dimethyl sulfate according to the method of Example I to form 1-methyl-2-n-decy1-4,5-dihydroimidazole.

EXAMPLE IV 1-methyl-2-n-dodecyl-4,5-dihydroimidaz0le CH2NCH3 CH5 C--CH2.(CHa)m.CH.-1

A mixture of 162 grams'of the methyl ester of tridecanoic acid was reacted with grams of anhydrous ethylene diamine according to the method of Example I. The resulting N-tridecanoyl ethylene diamine was condensed with anhydrous calcium oxide according to the method of Example I to form 2-11-dodecyl-4=.5 dihydroimidazole. This product was then reacted with dimethyl sulfate according to the method of Example I to form '1-methyl-2-n-dodecyl-4,5- dihydroimidazole. 1

EXAMPIE V 1 -ethyl-2-1z-dodccyl-el,S-dihydroimidaeole OH2--NC H2. CH3

This compound may be prepared by reacting 2-n-dodecyl-4=,5-dihydroimidaZole, prepared according to the method of Example IV, with diethyl sulfate according to the method of Example I using the stoichiometric'al proportions described therein.

' p 1 EXAMPLE v1 1-isopropyl-z-n-dodecyl 4,5-dihydroimidazole I OH! CHrN-OH I CH5 CH2 C-CH2.(CH2)m.CHa

This compound may be prepared by reacting 2-n-dodecyl-4,5-dihydroimidazole, prepared according to the method of Example IV, with isopropyl chloride according to the method of Ex ample II using the stoichiometrical proportions described therein.

This compound may be prepared by reacting Z-n-dodecyl-4,5-dihydroimidazole prepared according to the method of Example IV, with allyl bromide according to the method of Example If, using the stoichiometrical proportions described therein.

V I Emmett: vm 1 -methaZlyZ-2-n-dodecyl- 4,5-dz'hydroimidazole CHs-N'CHi-C gamma This compound may be prepared by reacting 2- n-dodecyl 4,5 dihydroimidazole, prepared according to the method of Example IV, with methallyl chloride according to the method of Example II, using the stoichiometrical proportions described therein.

EXAMPLE 1-methyl-2-n-tridecyZ-4,5-dihydroimidazole cH2-N-0Ha CH2 CCH2.(CH2)11.CH3

A mixture of 426 grams (1.5 moles) of n-butyl myristate and 270 grams (4.5 moles) of anhydrous ethylene diamine was -refluxed at 115 C'. for 1.10 hours. The;.excess ethylene diamine and the butanol resulting from theacylation were then distilled ofi,.the. distillation being -completed at a reduced pressure of mm. The crude product remaining in the still weighed 377 grams and melted at about 122 C. withflextensive previous softening. The product was identified as N-ntetradecanoyl ethylene diamine; the product was found to be appreciably soluble in benzene.

Amixture of 270 grams (1 mole) of crude N-ntetradecanoyl ethylene diamine and 280 grams (S'moles) of powdered calcium oxide was heated with agitation at.225e23 0-G. for 36 hours. The

mixture was then cooled and extracted with al-,

c0hol. The solvent was removed from the extract by-evaporation,-leaving 13Ggrams of crude amine base. The base-was distilled; yielding 70 grams of a paleryellow, crystalline, waxy solid material identified'as 2-'n tridecylimidazoline (2,-.ntri-.

d'ecy1-4,5-dihydroimidazole); M. B, 87-88" C; with slight previous softening. This product may then be reacted with dimethyl sulfate according EXAMPLE X 1 -methyl- Z-n-tetradecyl- 4,5 -dihydroimidazole CH2-N-CH3 C1112 CCH2.(CH2)12.CHa

This compound may be prepared by reacting a mixture of 183 grams of the methyl ester of pentadecanoic acid and 135 grams of ethylene diamine according to the method of Example I. Th resulting N -pentadecanoyl ethylene diamine was condensed with anhydrous calcium oxide according to the method of Example I to form 2- n-tetradecyl-4,5-dihydroimidazole. The product was reacted with dimethyl sulfate according to the method of Example I, using the stoichiometrical proportions described therein. The resulting product was 1-methyl-2-n-tetradecyl-4,5-dihydroimidazole.

It is desirable to use anhydrous ethylene diamine in the process described in this and other examples to facilitate the attainment of higher yields. However, ethylene diamine that is not substantially anhydrous may be employed.

6. EXAMPLEtXI 1methyl 2 n-pentadecyl-zi,5 dihydroimidazole:

cu ly-0H3 0H2 CH2.(OH2)11.CH3

A mixture of 193.5 grams of methyl p almitate was reacted with "gramsof anhydrous ethylene diamine according to the method of Example I. The resulting N-palmitoyl ethylene diamine wascondensed with anhydrous calcium oxide according to the method of Example I toform 2-hpentadecyl-4.5-dihydroimidazole. This product was reacted with dimethyl sulfate according to the method of Example I to form l-methyl-2-n penta-decyl-4,5-dihydroimidazole.

EXAMPLE XII 1 -methyl -2-n-hexadcyl- 4,5 dihydroimidazole This compound may be prepared by reacting a imixture of 204 grams of methyl margar'ate and 135 grams of anhydrous ethylene diamine according to the method of Example I. The resulting N-heptadecanoyl ethylene diamine is conto the method of Example. I to form Z-n-hexadecy1-4,5 -dihydroimidazole. This product is reacted with dimethyl sulfate according to the method of Example I to form 1-methyl-2-nhexadecyl-4,5-dihydroimidazole.

EXAMPLE XIII I 1 -methyZ-2- (n-undecen-I -yZ-1) -4,5-dih,'yd1'o- This compound may be prepared by reacting a mixture of 318 grams of the methyl ester of 2-ndodecenoic acid and 270 grams of anhydrous ethylene diamine according to the method of Example I. The resulting N-(n-d0decen-2-oyl-1) ethylene diamine may then be treated with anhydrous calcium oxide according to the method of Example I to form Z-(n-undecen-l-yl-l) -4,5-di hydroimidazole. This product may then be reacted with dimethyl sulfate according to the method of Example I to form 1-methyl-2(nun decen-l-yl-l) -4,5-dihydroimidazone.

032 %C CHCH.(CH2)10.CH:4

This compound may be prepared by reacting 1.5 moles of the methyl ester of Z-n-tetradecenoic acid with 4.5 moles of anhydrous ethylene diamine according to the method of Example I. The resulting N-(n-tetradecen- -oyl-1) ethylene diamine may then be treated with anhydrous calcium oxide according to the method of Example I to form Z-(n-tridecen-l-yl-l) -4,5-dihydroimidazole. This compound may then be reacted with allyl chloride as in Example VII according to the method of Example II to form l-allyl-2 -(n-tridecen-l-yl-l) -4,5-dihydroimidazole; and if didensed with anhydrous calcium oxide according 418,077 7 methyl sulfate is used as the alkylatmg agent the corresponding l-methyl compound is formed.

We claim: 1. Substituted dihydroimidazoles of the for- H mula type: 5

.CHP-N-CHI CH: -OH=CH.(CH2)10.CH:

5. The l-methyl 2 n-tridecy1-4,5-dihydroime idazole of the formula:

claim 1.

OHa--N-R N Number in which R represents an acyclic hydrocarbon radical having from 1 to 5 carbon atoms in its 2154922 structure and R1 represents a straight chain alkyl 25 226q965 radical having from 10 to 16 carbon atoms in its 2200815 structure. 2 004 864 3. The 1-methy1-2-n-undecyl-4,5 dihydroim- 2155377 idazole of the formula:

CHN CH 30 Number CH: CCH2.(CHz)s.OHa 501,727

6. Acid salts of the compounds defined in LUCAS P. KYRIDES. FERDINAND B. ZIENTY.

REFERENCES CITED The following references are of record ln th file of this patent: V

UNITED STATES PATENTS Name Date Chwala et a1. May '7, 1940 Chwala et a1 Aug. 13, 1940 Waldmann et a1. Apr. 18, 1939 Wilson Dec. 30, 1941 Ackley May 14', 1940 Graenacher et al, June 11, 1935 Waldmann Apr. 25, 1939 FOREIGN PATENTS Country Date British Feb. 28, 1939 OTHER REFERENCES Amer. Chem. Soc., Dec. 1935, pages 

